Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-23T16:40:39.745Z Has data issue: false hasContentIssue false
  • English
  • Français

Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy

Published online by Cambridge University Press:  03 September 2019

Adam C. Kean Open the ORCID record for Adam C. Kean [Opens in a new window] ,
Benjamin M. Helm ,
Matteo Vatta ,
Mark D. Ayers ,
John J. Parent  and
Robert K. Darragh
Adam C. Kean*
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Electrophysiology, Indiana University School of Medicine, Indianapolis, IN, USA
Benjamin M. Helm
Affiliation:
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Epidemiology, Fairbanks School of Public Health, Indiana University School of Medicine, Indianapolis, IN, USA
Matteo Vatta
Affiliation:
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
Mark D. Ayers
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Electrophysiology, Indiana University School of Medicine, Indianapolis, IN, USA
John J. Parent
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
Robert K. Darragh
Affiliation:
Department of Pediatrics, Division of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
*
Author for correspondence: Assistant Professor A. C. Kean, Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Electrophysiology, Indiana University School of Medicine, 705 Riley Hospital Drive, Riley Research Room 127, Indianapolis, IN 46202-5225, USA. Tel.: +1 317 274 8906; Fax: +1 317 274 4022; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Introduction:

The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.

Methods:

A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.

Results:

All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.

Conclusions:

There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.

Keywords

SCN5Asudden cardiac arrestdilated cardiomyopathy
Type
Original Article
Information
Cardiology in the Young , Volume 29 , Issue 10 , October 2019 , pp. 1257 - 1263
Check for updates
Copyright
© Cambridge University Press 2019 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

These authors contributed equally to this work.

References

Bezzina, CR, Rook, MB, Groenewegen, WA, et al. Compound heterozygosity for variants (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res 2003; 92: 159–168.CrossRefGoogle Scholar
McNair, WP, Ku, L, Taylor, MR, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004; 110: 2163–2167.CrossRefGoogle ScholarPubMed
McNair, WP, Sinagra, G, Taylor, MR, et al. Familial Cardiomyopathy Research Group. SCN5A variants associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J Am Coll Cardiol 2004; 57: 2160–2168.CrossRefGoogle Scholar
Meadows, LS, Isom, LL. Sodium channels as macromolecular complexes: implications for inherited arrhythmia syndromes. Cardiovasc Res 2005; 15: 448–458.CrossRefGoogle Scholar
Olson, TM, Michels, VV, Ballew, JD, et al. Sodium channel variants and susceptibility to heart failure and atrial fibrillation. JAMA 2005; 293: 447–454.CrossRefGoogle Scholar
Aronsen, JM, Swift, F, Sejersted, OM. Cardiac sodium transport and excitation-contraction coupling. J Mol Cell Cardiol 2013; 61: 11–19.CrossRefGoogle ScholarPubMed
Black, JA, Waxman, SG. Noncanonical roles of voltage-gated sodium channels. Neuron 2013; 16: 280–289.CrossRefGoogle Scholar
Remme, CA. Cardiac sodium channelopathy associated with SCN5A variants: electrophysiological, molecular, and genetic aspects. J Physiol 2013; 591: 4099–4116.CrossRefGoogle Scholar
Shy, D, Gillet, L, Abriel, H. Cardiac sodium channel NaV1.5 distribution in myocytes via interacting proteins: the multiple pool model. Biochem Biophys Acta 2013; 1833: 886–894.CrossRefGoogle ScholarPubMed
Savio-Galimberti, E, Argenziano, M, Antzelevitch, C. Cardiac arrhythmias related to sodium channel dysfunction. Handb Exp Pharmacol 2018; 246: 331–354.CrossRefGoogle ScholarPubMed
Ackerman, MJ, Priori, SG, Willems, S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Europace 2011; 13: 1077–1109.CrossRefGoogle ScholarPubMed
Richards, S, Aziz, N, Bale, S, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–424.CrossRefGoogle ScholarPubMed
Kelly, MA, Caleshu, C, Morales, A, et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel. Genet Med 2018; 20: 351–359.CrossRefGoogle ScholarPubMed
Makiyama, T, Akao, M, Tsuji, K, et al. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol 2005; 46: 2100–2106.CrossRefGoogle ScholarPubMed
Gui, J, Wang, T, Jones, RP, et al. Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome. PLoS One 2010; 5: e10985.CrossRefGoogle ScholarPubMed
Kapplinger, JD, Tester, DJ, Alders, M, et al. An international compendium of mutations in SCN5A-encoded cardiac sodium channel in patients referred to Brugada syndrome genetic testing. Heart Rhythm 2010; 7: 33–46.CrossRefGoogle ScholarPubMed
Francis, J, Antzelevitch, C. Atrial fibrillation and Brugada syndrome. J Am Coll Cardiol 2008; 51: 1149–1153.CrossRefGoogle ScholarPubMed
Vorobiof, G, Kroening, D, Hall, B, et al. Brugada syndrome with marked conduction disease: dual implications of a SCN5A mutation. Pacing Clin Electrophysiol 2008; 31: 630–634.CrossRefGoogle ScholarPubMed
Rodriguez-Manero, M, Namdar, M, Sarkozy, A, et al. Prevalence, clinical characteristics and management of atrial fibrillation in patients with Brugada syndrome. Am J Cardiol 2013; 111: 362–367.CrossRefGoogle ScholarPubMed
Hassel, D, Dahme, T, Erdmann, J, et al. Nexilin variants destabilize cardiac Z-discs and lead to dilated cardiomyopathy. Nat Med 2009; 15: 1281–1288.CrossRefGoogle Scholar
Wang, H, Li, Z, Wang, J, et al. Variants in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy. Am J Hum Genet 2010; 87: 687–693.CrossRefGoogle Scholar
Aherrahrou, Z, Schiossarek, S, Stoelting, S, et al. Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis. Basic Res Cardiol 2016; 111: 6.CrossRefGoogle ScholarPubMed
Pardun, E, Wenzel, K, Kramer, HH, Berger, F, Geruli, B, Klaassen, S. Nexilin mutations are associated with left ventricular noncompaction cardiomyopathy. Mol Cell Pediatr 2015; 2 (Suppl 1): A7.CrossRefGoogle Scholar
Amendola, LM, Jarvik, GP, Leo, MC, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research consortium. Am J Hum Genet 2016; 98: 1067–1076.CrossRefGoogle ScholarPubMed
Nykamp, K, Anderson, M, Powers, M, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 2017; 19: 1105–1117.CrossRefGoogle ScholarPubMed
Tavtigian, SV, Greenblatt, MS, Harrison, SM, et al. Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genet Med 2018; 20: 1054–1060.CrossRefGoogle ScholarPubMed
Belkaya, S, Kontorovich, AR, Byun, M, et al. Autosomal recessive cardiomyopathy presenting as acute myocarditis. J Am Coll Cardiol 2017; 69: 1653–1665.CrossRefGoogle ScholarPubMed
Kennedy, L, Kaltenbrun, E, Greco, TM, et al. Formation of a TBX20-CASZ1 protein complex is protective against dilated cardiomyopathy and critical for cardiac homeostasis. PLoS Genet 2017; 13: e1007011.CrossRefGoogle ScholarPubMed
Nair, NU, Das, A, Amit, U, et al. Putative functional genes in idiopathic dilated cardiomyopathy. Sci Rep 2018; 8: 66.CrossRefGoogle ScholarPubMed
Burkett, EL, Hershberger, RE. Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005; 45: 969–981.CrossRefGoogle ScholarPubMed
Hasselberg, NE, Haland, TF, Saberniak, J, et al. Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation. Eur Heart J 2018; 39: 853–860.CrossRefGoogle Scholar
Lehmann, HI, Meltendorf, U, Klein, HU. Long-term follow-up of permanent atrial standstill in a German family with mutation in the SCN5A gene. Heart Rhythm Case Rep 2018; 4: 356–358.Google Scholar
Tan, RB, Gando, I, Bu, L, Cecchin, F, Coetzee, W. A homozygous SCN5A mutation associated with atrial standstill and sudden death. Pacing Clin Electrophysiol 2018; 41: 1036–1042.CrossRefGoogle Scholar
Supplementary material: File

Kean et al. supplementary material

Kean et al. supplementary material

Download Kean et al. supplementary material(File)
File 16.5 KB